Structure of 35231-56-2
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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
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Batch number can be found on the product's label following the word 'Batch'.
Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.
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CAS No. : | 35231-56-2 |
Formula : | C5H6N2O |
M.W : | 110.11 |
SMILES Code : | CC1=NC=C(C=N1)O |
MDL No. : | MFCD09879706 |
InChI Key : | OHFVPBGSKPYIED-UHFFFAOYSA-N |
Pubchem ID : | 535857 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 8 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.2 |
Num. rotatable bonds | 0 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 29.02 |
TPSA ? Topological Polar Surface Area: Calculated from |
46.01 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.03 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
0.25 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
0.49 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
-0.72 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
0.92 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
0.39 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.24 |
Solubility | 6.41 mg/ml ; 0.0582 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-0.78 |
Solubility | 18.4 mg/ml ; 0.167 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-1.4 |
Solubility | 4.36 mg/ml ; 0.0396 mol/l |
Class? Solubility class: Log S scale |
Soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
Yes |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
No |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-6.79 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
1.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
0.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
1.27 |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | Preparation of D17:The bis-sulfone 2 (11.80 g, 17.23 mmol) was dissolved in NMP (60 mL), followed by adding 2-methylpyrimidin-5-ol 1 (7.59 g, 68.93 mmol). The homogeneous solution was obtained. K2CO3 (9.53 g, 68.93 mmol) was added and the resulting suspension was heated to 100 C for 1 hr, then Boc protected amine (7.32 g, 34.46 mmol) was added and the resulting mixture was heated to 100 C for one more hour, cooled to the room temperature and water (450 mL) was poured into the mixture with stirring. The mixture was cooled to 0 C, filtered and washed the precipitates with water (2×25 mL), dried to give about 12 g of the white solid crude product. The crude solid was dissolved in dichloromethane and silica gel was added. Solvents were removed. Flash chromatography of the residue over silica gel (EtOAc/hexane: 20% to 50% to 90%) to give the pure D17 as a white solid (7.76 g, 75%). LC-MS: M+1: 635.30. | |
75% | General procedure: Example 9 Synthesis of Formula 1 compounds where L=Q and R8 is NHalkyl General Scheme for the bis-sulfone Route: D14 D15 D16 [0518] Tert-buty 2-amino-3-cyano-5-fluoro-lH-indol-7-yl(methyl)carbamate (D13): Crude tert-butyl 3,5-difluoro-2-nitrophenyl(methyl)carbamate (C3) (46.12 g, 0.162 mol) was dissolved in DMF (80 ml) and cooled in an ice-water bath. To it was added malononitrile (1 1.8 g, 179 mmol) followed by the addition of the NaOH solution (12.98 g, 325 mmol) in water (20 ml). After the exothermic reaction mixture was stirred for one hour, the ice-water bath was removed and the reaction was stirred for another one hour. It was then diluted with DMF (80 ml) and water (80 ml), and the atmosphere was displaced with argon. Sodium bicarbonate (109 g, 1.3 mol) followed by sodium hydrosulfite (123 g, 649 mmol) was added. The mixture was well stirred under argon at 40 C for 12 hours (Additional sodium hydrosulfite could be added if the reaction took longer time to complete). After the reaction was cooled down to room temperature, it was diluted with EtOAc (100 ml) and then filtered through a fritted glass funnel. The solids were washed with EtOAc/hexane (1 : 1, 400 ml). The aqueous layer was separated, and the organic layer was extracted with 10% buffer 7 solution (3x 100 ml). The combined aqueous layers were back extracted with EtOAc/hexane (1 : 1, 200ml). The combined organic phases was washed with 5% K2CO3 solution (300 ml). The extractions were then dried over sodium sulfate and concentrated by rotary evaporation to afford the crude compound (D13) as brown color solid (32.6 g, 66 %). LC-MS : M+l : 305.16. [0519] 1H NMR (DMSO, 300 MHz): delta = 10.77 (s, 1H), 6.84-6.80 (m, 1H), 6.69 (s, 2H), 6.69-6.66 (m, 1H), 3.14 (s, 3H), 1.33 (s, 9H). [0520] Tert-buty 2,4-bis(benzylthio)-6-fluoro-9H-pyrimido[4,5-Z>]indol-8- yl(methyl)carbamate (D15): Crude /er/-butyl 2-amino-3-cyano-5-fluoro-lH-indol-7- yl(methyl)carbamate (D13) (4 g, 13.14 mmol), sodium hydroxide (756 mg, 18.9 mmol), and EtOH (40 ml) were added in a 350ml seal tube. The mixture was stirred at 50 C for 15mins to dissolve all NaOH and then cooled down to room temperature. After the atmosphere was displaced with argon, the solution was added with carbon disulfide (10 ml) and dimethyl sulfoxide (1 ml). The reaction was stirred at room temperature for lhour then refluxed at 80 C for 42 hours. It was then cooled down to room temperature and placed in an ice-water bath. Water (20 ml) was added followed by the addition of benzyl chloride (3.33 g, 26.27 mmol). The ice-water bath was removed, and the reaction was stirred at ambient temperature for 5 hours. An additional of benzyl chloride (1.66 g, 13.13 mmol) was added, and the resulting solution was stirred at room temperature overnight. It was diluted with EtOAc (60 ml) and water (100 ml). The resulting solution was partitioned into two layers, and the aqueous phase was removed through an extraction funnel and back extracted with 50 ml of ethyl acetate. The combined organic layers were concentrated by rotary evaporation, and the residue was purified through silica gel column chromatography (15 % EtOAc in hexane) to afford the tile compound (D15) as yellow foam (2.65 g, 36%). LC-MS : M+l : 561.05. [0521] 1H NMR (CDC13, 300 MHz): delta = 8.72 (s, 1H), 7.66-7.62 (dd, J = 8.37, 2.28 Hz, 1H), 7.48-7.27 (m, 10H), 7.05-7.01 (dd, J = 10.14, 2.28 Hz, 1H), 4.69 (s, 2H), 4.55 (s, 2H), 3.37 (s, 3H), 1.48 (s, 9H). [0522] Tert-buty 2,4-bis(benzylsulfonyl)-6-fluoro-9H-pyrimido[4,5-Z>]indol-8- yl(methyl)carbamate (D16): The solution of tert-bu yl 2,4-bis(benzylthio)-6-fluoro-9H- pyrimido[4,5-6]indol-8-yl(methyl)carbamate (D15) (2.28 g, 4.07 mmol) in DCM (50 ml) was cooled in an ice-water bath and added with 3-chloroperoxybenzoic acid 77 % (2.01 g, 8.95 mmol). After the reaction was stirred for 1 hour, the ice-water bath was removed and an additional mCPBA (2.01 g) was added. The resulting solution was stirred at ambient temperature for 7 hours. It was then extract with 5% K2CO3 solution (100 ml), and the aqueous layer was back extracted with DCM (100ml). The combined organic layers were washed first with 5% K2C03 (100 ml) then with 5% NaCl solution (50 ml). It was dried over sodium sulfate and concentrated by rotary evaporation to afford the crude title compound (D16) as bright yellow solid (2.54 g, quantitative yield). LC-MS : M+l : 625.05. [0523] 1H NMR (CDCI3, 300 MHz): delta = 10.07 (s, 1H), 8.49-8.46 (dd, J = 8.64, 2.22 Hz, 1H), 7.54-7.51 (m, 1H), 7.38-7.27 (m, 10H), 4.95 (s, 2H), 4.84 (s, 2H), 3.40 (s, 3H), 1.52 (s, 9H). Scheme: D16 D17 D18 (4.069) [0524] Preparation of D17: The bis-sulfone 2 (1 1.80 g, 17.23 mmol) was dissolved in NMP (60 mL), followed by adding 2-methylpyrimidin-5-ol 1 (7.59 g, 68.93 mmol). The homogeneous solution was obtained. K2CO3 (9.53 g, 68.93 mmol) was added and the resulting suspension was heated to 100 C for 1 hr, then Boc protected amine (7.32 g, 34.46 mmol) was added and ... |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.182 g | EXAMPLE 12: Synthesis of Prodrugs at R (5)-2-Amino-A^-(4-((R)-7-amino-5-azaspiro[2.4]heptaii-5-yl)-6-fluoro-2-(2- methylpyrimidiii-5-yloxy)-9H-pyrimido[4.5-Z>]indol-8-yl)-A7-methylpropanamide D16 D77 D78 D79 D80 (4.423) [0576] The mixture of D16 (1.00 g, 1.46 mmol) in trifluoroacetic acid (3.0 mL) was stirred for 30 min at 23 C. Trifluoroacetic acid was evaporated by reduced pressure to provide D77 (quantitative yield) as deep orange solid. This crude material was used for next reaction without further purification. LC/MS (ESI, M+H+) = 585. The mixture of D77 (0.292 g, 0.50 mmol), 2-methylpyrimidin-5-ol (0.165 g, 1.50 mmol) and K2C03 (0.276 g, 2.00 mmol) in NMP (5.0 mL) was stirred for 2 hr at 100 C. After being stirred for 2 hr, the reaction was checked by LC/MS. (R)-tert-bu yl 5-azaspiro[2.4]hepten-7-ylcarbamate (0.318 g, 1.50 mmol) was added at once, the mixture was allowed to stir for 1 hr 30 min at 100 C. The resulting heterogeneous mixture was cooled to 23 C and purified by HPLC to provide D78 (0.182 g, 0.34 mmol) as yellow solid. LC/MS (ESI, M+H+) = 535. To a solution of D78 (0.182 g, 0.34 mmol) and K2C03 (0.094 g, 0.68 mmol) in CH2C12 (10.0 mL) was added (5)-2-(l,3-dioxoisoindolin-2-yl)propanoyl chloride (0.161 g, 0.68 mmol) dissolved in CH2C12 (2.0 mL) at 23 C. The mixture was allowed to stir for 2 hr at 60 C and then cooled to 23 C. The reaction mixture was concentrated by Rotavap and the crude material was purified by HPLC to give D79 as yellow solid. LC/MS (ESI, M+H+) = 736. To a solution of D79 in ethanol (7.0 mL) was added hydrazine (1.5 mL, 30 wt. % solution in water) via syringe at 23 C. The mixture was stirred for 1 hr at 23 C. The reaction mixture was concentrated by Rotavap and the crude material was purified by HPLC to provide 5 as light yellow solid. LC/MS (ESI, M+H+) = 606. The mixture of 5 in trifluoroacetic acid (1.50 mL) was stirred for 30 min at 23 C. The crude material was purified by HPLC to provide a title compound D80 (0.031 g, 0.061 mmol) as white solid. LC/MS (ESI, M+H+) = 506. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With di-tert-butyl-diazodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 120℃; for 8h; | DBAD (CAS: 870-50-8; 1.36 g, 5.90 mmol) was added to a mixture of 2- methylpyrimidin-5-ol (CAS: 35231-56-2; 500 mg, 4.54 mmol), (7?)-(-)-N-boc-3- pyrrolidinol (CAS: 109431-87-0; 1.11 g, 5.90 mmol) and triphenylphosphine (1.55 g, 5.90 mmol) in THF (10 mL). The reaction mixture was stirred at room temperature for 18 h and concentrated to dryness. The residue was purified by flash column chromatography (silica, EtOAc in heptane, gradient from 0/100 to 100/0). The desired fractions were collected and concentrated in vacuo to yield intermediate 32 (1.1 g, 87%) as a colorless oil. |
A126636 [100991-09-1]
2-(Trifluoromethyl)pyrimidin-5-ol
Similarity: 0.79
A126636 [100991-09-1]
2-(Trifluoromethyl)pyrimidin-5-ol
Similarity: 0.79